Research Summary The design of new synthetic methods has a broad impact on biomedical research. Many factors are involved in the selection of a compound as a potential drug candidate, but one that is critical, but not always articulated, is whether or not a potential target is accessible. If a compound cannot be made in a practical way either through synthesis or from biological sources, then it will never become a viable pharmaceutical agent. Consequently, truly powerful and previously unprecedented synthetic methods can open up vistas of novel structural scaffolds for exploration as potential drug targets. The central goal of this research program is to develop new strategic reactions that will have broad impact in organic synthesis. Rhodium-stabilized carbenoids containing both donor and acceptor groups are capable of a range of synthetically useful transformations. This proposal focuses on a new direction of study of donor/acceptor carbenoids, namely enantioselective transformations of rhodium-bound zwitterionic intermediates. The full scope of these new synthetic methods will be explored and then applied to the synthesis of biologically relevant natural products and important pharmaceutical drug scaffolds.